Serine hydrolases represent one of the largest and most diverse families of enzymes in higher eukaryotes, comprising numerous serine proteases, lipases, esterases, and amidases. Human neutrophil elastase is a kind of serine hydrolase released from the granules of neutrophil, which appear in the cases of infections or inflammatory diseases. Neutrophil elastase is an enzyme hydrolyzing proteins such as elastin, collagen, proteoglycan, fibronectin and others which constitute the interstitum of intravital connective tissues such as lung, cartilage, vascular wall and skin. In addition, it has been clarified that neutrophil elastase acts on other proteins or cells as well.
In the living body, serine hydrolases, such as neutrophil elastase keeps the homeostasis of the living body while the activities thereof are controlled by endogenous inhibitor proteins such as α1-protease inhibitor, α2-macrogloblin and secretory leukocyte protease inhibitor. However, when a balance between neutrophil elastase and the endogenous inhibitors is lost by the excessive release of neutrophil elastase in the inflammation site or by the lowering in the inhibitor level, the control of neutrophil elastase activities cannot be kept, by which tissues are injured.
Diseases in which serine hydrolase, including neutrophil elastase may participate are, for example, pulmonary emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome (ARDS), idiopathic interstitial pneumonia (IIP), cystic pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, chronic sinopulmonary infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, joint scleroma, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection against organ transplant, premature amniorrhexis, bullous dermatosis, shock, sepsis, systemic lupus erythematosus (SLE), Crohn's disease, disseminated intracapillary coagulation (DIC), tissue injury after ischemia-reperfusion, formation of cornea cicatricial tissue, myelitis and others.
Therefore, there is a need for effective serine hydrolase inhibitors as therapeutics for treatment of serine hydrolase-mediated diseases.